Medicine and Health Sciences Commons^™

Matriptase Mediated C-Met Signaling In Breast Cancer, Gina Lynn Zoratti

Wayne State University Dissertations

MATRIPTASE MEDIATED c-MET SIGNALING IN CRITICAL FOR BREAST CANCER PROGRESSION

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GINA ZORATTI

Historically proteases have been associated with tumor progression and metastasis through degradation of the basement membrane. However, in recent years these enzymes have also been shown to play key roles in the activation of growth factors and cytokines, thereby activating pro-oncogenic signaling pathways. Matriptase (MT-SP1, ST14) is an epithelia-specific pericellular protease which has received considerable attention in recent years spurred by the consistent dysregulation of the protease in human epithelial tumors including breast cancer. We have performed both functional and mechanistic studies of matriptase in breast cancer …

Combating Resistance To Epidermal Growth Factor Recpetor Inhibitors In Triple Negative Breast Cancer, Julie Marie Madden

Wayne State University Dissertations

Triple negative breast cancer (TNBC) patients suffer from a highly malignant and aggressive cancer that lacks an effective targeted therapeutic. Although many TNBCs, both in vitro and in vivo, have increased expression of epidermal growth factor receptor (EGFR), EGFR targeted inhibitors, such as gefitinib (GEF), have yet to demonstrate efficacy. Using mass spectrometry to identify pathways that remain activated in the presence of GEF, we found that components of the mTOR signaling pathway remain phosphorylated. While inhibiting mTOR with temsirolimus (TEM) decreased mTOR signaling, EGFR signaling pathways remained activated and the TNBC cell lines continued to proliferate. However, dual treatment …

Isolation And Characterization Of Natural Alpha-Glucosidase Inhibitors From Antioxidant Rich Red Wine Grapes (Vitis Vinifera), Hoda Chaouki Kadouh

Wayne State University Dissertations

Background: Diabetes is currently a global public health problem affecting people at all ages. Dietary antioxidants have been associated with a reduced risk of type 2 diabetes. Grape pomace contains considerable amounts of polyphenols and it has been reported to exhibit an inhibitory activity against alpha- glucosidases. Alpha-glucosidases, in turn, play a major role in controlling starch digestion and therefore postprandial blood glucose, a target for diabetes management.

Objective: This study aims to investigate the anti-diabetes potential of a selection of six grape pomaces and prepare and purify active components in the active variety that specifically inhibit intestinal alpha-glucosidases. The …

Metabolic Syndrome In Obese African American Adolescents, Yulyu Yeh

Wayne State University Dissertations

Limited research regarding metabolic syndrome (MetS) has been conducted in obese African American adolescents (OAAA) using the International Diabetes Federation IDF criteria. MetS is a constellation of risk factors that increase the risk for chronic diseases and is defined as presence of any 3 or more of the 5 criteria: fasting glucose 100mg/dl, waist circumference 90th percentile, triglycerides 150 mg/dl, blood pressure (BP) 130/85 mmHg and HDL < 40mg/dl. The aim of this study was to assess the incidence of MetS in OAAA by using the IDF criteria and the relationship with diet, fast food consumption, nutrition knowledge, home food environment (HFE), and serum calcium, leptin, 1,25-dihydroxy vitamin D (1, 25 D3) levels. One hundred and fifty one OAAA (mean age: 14.3 ± 1.4 years, 65.6% girls, mean BMI: 37.4±7.2 kg/m2) in a metropolitan area took part in this study. Anthropometric data and fasting blood samples were collected. Participants completed a set of questionnaires regarding diet, fast food consumption, and nutrition knowledge. HFE was completed by the care givers. The MetS rate for OAAA was 61.6% and boys had higher MetS than girls (73.1%, 55.6% respectively). OAAA without MetS had higher serum calcium and 1,25 D3 level but no significant difference were found in food consumption, nutrition knowledge, and HFE. Total cholesterol /HDL ratio and Insulin resistance increased the odds of MetS by 55% and 10% and 1,25 D3 decrease the odds of MetS by 2%. Even though high fast food consumption, lack of nutrition knowledge and poor food environment were negatively associated with obesity, they didn't contribute to MetS. Increase serum vitamin D and calcium level might be beneficial to reduce MetS in OAAA population.

Cervical Remodeling/Ripening At Term And Preterm Delivery: The Same Mechanism Initiated By Different Mediators And Different Effector Cells, Juan Miguel Gonzalez Velez

Wayne State University Dissertations

Premature cervical remodeling/ripening is believed to contribute to preterm delivery (PTD), the leading cause of perinatal morbidity and mortality. Despite considerable research, the causes of term and PTD remain unclear, and there is no effective treatment for PTD. We tested the hypothesis that complement activation plays a role in cervical remodeling and PTD. We studied cervical remodeling at term.

We studied two mouse models of inflammation-induced PTD. The first model was induced by vaginal administration of lipopolysaccharide (LPS)and the second one by administration of progesterone antagonist RU486. Increased cervical C3 deposition and macrophage infiltration and increased serum C3adesArg and C5adesArg …

Blast-Induced Tinnitus: A Combined Behavioral, Memri, And Electrophysiology Study, Jessica Pengyun Ouyang

Wayne State University Dissertations

ABSTRACT

BLAST-INDUCED TINNITUS: A COMBINED BEHAVIORAL, MEMRE, AND ELECTROPHYSIOLOGY STUDY

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JESSICA OUYANG

May 2014 Advisor: Drs. Steve Cala & Jinsheng Zhang

Major: Physiology

Degree: Doctor of Philosophy

Tinnitus and hearing loss are the frequent auditory-related co-morbidities of blast trauma. The etiology of blast-induced tinnitus is also muddled by brain mechanisms associated with emotional and cognitive problems such as anxiety, memory loss, and depression. We set out to develop a realistic and ecologically valid model to address changes of cognitive status and psychological state that are associated with blast- induced tinnitus. In this study, 19 adult rats were randomly divided …

Molecular Studies On The Anti-Tumor Effects Of Metal-Based Complexes: Involvement Of The Ubiquitin-Proteasome And Apoptotic Pathways, Sara M. Schmitt

Wayne State University Dissertations

The ubiquitin-proteasome pathway is crucial to normal cellular function, and as such, has been extensively investigated as a potential target for cancer therapeutics. Many compounds have been tested for their proteasome inhibitory ability, including various small peptide aldehydes, and, following the success of cisplatin, several metal-containing complexes. The efficacy of these compounds in preclinical studies ultimately resulted in the development and approval of the first-in-class proteasome inhibitor bortezomib, the use of which, unfortunately, has been hindered by toxicity and resistance. These limitations have led to a massive push toward designing and developing new, less toxic proteasome inhibitors for clinical use. …

Proximate And Evolutionary Insights Into The Epigenetics Of Posttraumatic Stress Disorder, Levent Sipahi

Wayne State University Dissertations

Posttraumatic stress disorder (PTSD) is an important medical and social condition. Although the vast majority of individuals are exposed to traumatic events within their lifetime, a minority subsequently develop diagnosable PTSD. What underlies differential risk and resiliency in the face of trauma is an ongoing research and clinical question with implications for prevention and treatment. Recent work has revealed a putative role of epigenetic variation and modification - most notably DNA methylation - in the etiology of PTSD. That DNA methylation is stable, yet modifiable in response to lived experiences, makes it a strong candidate to mechanistically explain the ontogeny …

Linking Molecular, Electrical And Anatomical Properties Of Human Epileptic Brain, Shruti Bagla

Wayne State University Dissertations

Epilepsy is a common neurological disorder of recurrent unprovoked seizures. It affects almost 1% of the world population. Although there is a wide range of anti-epileptic drugs (AEDs) available, they only treat the seizure symptoms and do not cure the disease itself. The poor role of AEDs can be attributed to the lack of knowledge of exact mechanisms and networks that produce epileptic activities in the neocortex. At present, the best cure for epilepsy is surgical removal of electrically localized epileptic brain tissue. Surgically removed brain tissue presents an excellent opportunity to discover the molecular and cellular basis of human …

Tmprss2-Erg Regulation Of Androgen Biosynthetic Enzyme Expression, Dht Synthesis, And Androgen Receptor Activation In Prostate Cancer, Katelyn Ann Powell

Wayne State University Dissertations

Intratumoral androgen synthesis in prostate cancer (PCa) contributes to the development of castration-resistant prostate cancer (CRPC). Several enzymes responsible for androgen biosynthesis have been shown to be overexpressed in CRPC, thus, contributing to CRPC in a castrated environment. Although intratumoral androgen synthesis is thought to contribute to the development and progression of CRPC, currently little is known regarding the regulation of androgen biosynthetic enzyme gene expression in PCa. The TMPRSS2-ERG transcription factor has been shown to be present in primary PCa tumors as well as CRPC tumors. The hypothesis was investigated that TMPRSS2-ERG fusions regulate androgen biosynthetic enzyme (ABE) gene …